A National Medical Cyclotron Facility

RU8G08400

A NATIONAL MEDICAL CYCLOTRON FACILITY

REPORT TO THE MINISTER OF HEALTH BY THE MEDICAL CYCLOTRON COMMITTEE

Oct. 31 1985 A NATIONAL MEDICAL CYCLOTRON FACILITY

A report to the Minister of Health by the Medical Cyclotron Committee

EXECUTIVE SUMMARY

1. INTRODUCTION - Cyclotron - produced radioisotopes and their applications - Background to the medical cyclotron study - Approach to the medical cyclotron study - Proposals for medical cyclotron facilities - Options considered by the Committee - Nature of nuclear medicine

2. BENEFITS TO RESEARCH AND TRAINING - Scope and benefits of PET research - SPECT research - Labelling of monoclonal antibodies - Receptor-specific imaging tracers - Fundamental research - Training - Research and training benefits

3. BENEFITS TO PATIENT CARE - Improved availability of currently Imported isotopes - Benefits of iodine-123 . brain studies . thyroid studies . renal studies - Benefits of krypton-Blm - Clinical applications of PET 4. COSTS ASSOCIATED WITH A MEDICAL CYCLOTRON FACILITY - -Capital and operating costs - Markets and revenue for cyclotron-produced radiosotopes - Export market - Economic appraisal - net present values - Costs to the health care system - Savings for the health care system - Costs of continuing without a cyclotron

5. SITING AND MANAGEMENT - Advantages of processing/distribution by AAEC - Hospital associated research - Board of management 6. CONCLUSIONS AND RECOMMENDATIONS

Oct 31 1985 EXECUTIVE SUMMARY

The Committee recommends the establishment of a national medical • cyclotron to provide a supply of short-lived radioisotopes for research in relevant fields of medicine, and for diagnostic use in nuclear medicine.

Research and training in nuclear medicine in Australia are both limited by the lack of a medical cyclotron facility. In addition there are other fields of medical research where Australia has an eminent position and where the availability of cyclotron produced isotopes is important to their continued excellence.

An Australian cyclotron would provide benefits in routine patient management by making available for diagnostic use short-lived isotopes not presently available, or only available as imports with some supply problems; however the magnitude of this benefit is not quantifiable. Methods of management devised as a result of Australian or overseas studies using short-lived isotopes might also be used to the benefit of other patients who may not need the same investigations.

The cyclotron facility should be established at a teaching hospital in the expectation that the associated medical faculty will support appropriate teaching and research programs to exploit adequately its potential.

Advantage should be taken of the existing experience within the Commercial Products Unit of the Australian Atomic Energy Commission, which should be responsible for the preparation and distribution of cyclotron produced isotopes, as an extension of its present role in the supply of reactor produced isotopes.

The Royal Prince Alfred Hospital is seen as the most appropriate teaching hospital for the cyclotron facility. The estimated capital cost of the cyclotron facility (March 1985) 1s Wl.O, with annual recurring costs of approximately $M2.5. These •figures Include the capital and operating costs of equipment for » 'positron emission tomography (PET), to be deployed at the cyclotron facility, using very short lived Isotopes. The Committee believes that PET 1s likely to develop as a research and diagnostic tool of * great Importance 1n the future although Its major Influence 1n the Immediate future will be 1n research. It also considers that the availability of fluorlne-18 from the cyclotron could provide a satisfactory basis for PET studies at other locations 1n the short term. • The cyclotron facility should be administered by a manager and staff t responsible to a Board of Management drawn from the user community and other relevant Institutions. Research associated with the cyclotron should be subject to peer review and should compete for funding support 1n the normal way.

The Committee recognises that a proposal for a medical cyclotron must be assessed in the context of competing requests for resources to support medical research and health services. However we believe that a sound case exists and recommend that preparation for construction commence as soon as possible. 1. INTRODUCTION

Cyclotron-Produced Raololsotopes and their Applications »* ' - , A cyclotron 1s a machine designed to produce high energy beams of charged m i atomic particles. By bombarding suitable targets with a particle beam from a cyclotron, certain radlolsotopes with slgnd leant diagnostic and research applications can be produced. These cannot ba produced, or are produced only with great difficulty, by a nuclear reactor. Host have unstable, neutron-deficient nuclei and are relatively short-lived. At present there is no medical cyclotron in Australia.

• Cyclotron-produced radlolsotopes fall 'into two categories, photon emitters and positron emitters. A number of the photon-emitting radioisotopes have diagnostic applications in nuclear medicine and can be used with equipment currently available in Australian nuclear medicine Departments.

Three of these are sufficiently long-lived to allow their Import into Australia. They are:

gallium-67, used in the detection of abscesses, inflammation and tumours;

thall1um-20l, used principally in heart studies;

indium-Ill, used to label blood cslls and monoclonal antibodies, and in studies of cerebral spinal fluid.

Of those which are too short-livecJ to be imported, the most significant ar.:

iodine-123 (half-life 13 hours), with major applications in studies of the thyroid, brain and kidney; and

krypton-Sim, a very short-lived isotope (half-life 13 seconds) produced 1n a generator from the cyclotron radioisotope rubidium-81 whose short half-life (4.7 hours) does not permit Importation. Krypton-Sim is used in lung studies, particularly for the diagnosis of pulmonary Positron-emitting radlolsotopes are used In the new Imaging technique of positron emission tomography (PET) for which special Instrumentation 1s required. PET 1s a high resolution technique which allows the study of biochemical and physiological processes rather than purely anatomical structures. It has been applied particularly to brain studies and has been used for example 1n the quantitative study of cerebral blood flow, glucose metabolism, oxygen utilization, and neuro-transmltter and drug distribution although at present 1t finds application only 1n research fields.

Cyclotron-produced radlolsotopes used 1n PET Include carbon-11, oxygen-15, and nltrogen-13, which are so short-lived that they must be used very close to the site of production. The longer-lived fluorine-18 is also widely used in PET studies, and could be used at a site up to 6 hours travelling time from the cyclotron.

Background to the Medical Cyclotron Study For a numbe'r of years the desirability of establishing a med.ical cyclotron in Australia has been discussed. Late in 1983 the Australian Atomic Energy Commission and the Austin Hospital submitted new proposals for centres incorporating medical cyclotron facilities to the Commonwealth Government. Subsequently the Minister for Health asked the National Health Technology Advisory Panel (NHTAP) to advise on the cost effectiveness and desirability of a national medical cyclotron facility. After d preliminary examination the Panel concluded that a detailed technical and economic- study would be necessary to determine the costs and benefits for Australian health care of medical cyclotron facilities. The Panel also felt that research applications might turn out to offer the main justification for a medical cyclotron, and recommended that this aspect be examined further by the NH and HRC.

In the 1984-85 Budget the Commonwealth Government provided funding for a study along the lines recommended by the NHTAP. In September 1984, a Medical Cyclotron Committee was established to manage the study. Its membership and terms of reference are at Appendix 1.

Approach to the Medical Cyclotron Study The Committee saw its central task as establishing whether there was a need for medical cyclotron facilities in Australia. The benefits identified would then need to be weighed against the costs, taking into account benefits to research and training as well as for patient care. To assist 1t 1n the study, and 1n line with the recommendations of the National Health Technology Panel (NTHAP 1984) the Committee decided to draw on expertise 1n the specific technologies under Investigation, Including their potential for medical research, technology evaluation, and 1n economics and marketing. The Committee Identified three studies which should be undertaken by consultants with the appropriate expertise:

costs and benefits for Australian health care and research of cyclotron radlolsotope production; • • > , costs and benefits for Australian health care and research of positron emission tomography;

financial analysis of options for medical cyclotron facilities.

The terms of reference of the three studies are at Appendix 2. The first two studies were undertaken by Dr E.J. Potchen and Mr D. Gift, of Michigan State University, U.S.A. The Australian firm of Ian Turner and Partners was engaged to undertake the third study. Final reports were received from the consultants in March 1985, and were drawn on extensively 1n the preparation of this report.

Valuable inputs into the study were also obtained from the Medical Cyclotron Workshop, convened in Canberra in December 1984, through the contributions of Australian nuclear medicine physicians, medical researchers, and those with experience in the management of medical cyclotron facilities and in the evaluation of their impact on research and health care in other countries. Dr Potchen of Michigan State University and Mr D D Vonberg of the British Medical Research Council Cyclotron Unit made valuable contributions in ' this respect.

Cyclotrons have been used for many years for the production of neutron beams for use in cancer therapy. The Committee supports the opinion of the NHTAP that the effectiveness of this procedure compared with other forms of therapy was still being evaluated in overseas studies and that the technique should therefore not be considered at this stage.

Proposals for Medical Cyclotron Facilities In the course of the study revised proposals for medical cyclotron facilities were put forward by the AAEC and the Austin Hospital. They were both considered carefully by the Committee. t: . The AAEC proposed a dual purpose facility at Royal Prince Alfred Hospital, Incorporating:

a 40 HeV cyclotron for the production of photon-emitting radioisotopes for processing and distribution to nuclear medicine centres, as well as the production of fluorine-18 for use 1n PET studies elsewhere in Australia and production of other positron emitting Isotopes for on-site use.

a national nuclear medicine/PET centre for research, training and evaluation of clinical benefits. '

The Austin Hospital proposed the establishment on its own premises of a PET centre with a 16 HeV cyclotron dedicated to the production of positron emitting isotopes. The Hospital also suggested that a 40 HeV cyclotron for the production of photon-emitting radioisotopes for use in nuclear medicine could be installed back-to-back with the 16 HeV cyclotron, although possibly under the management of another body. During the preparation of this report, the Committee received advice of a modification to their proposal in favour of a compact 11 HeV cyclotron specifically designed for production of radiopharmaceuticals for PET scanners.

Options Considered by the Committee The Committee considered the following possibilities:

continue without a medical cyclotron

establish a cyclotron for commercial radioisotope production only

establish a facility for PET only

I establish a combined radioisotope production/PET facility

establish separate radioisotope production and PET facilities, each with its own dedicated cyclotron

The Committee considers that the combined radioisotope production/PET facility would be the most appropriate for Australia. 8 'Nature of Nuclear Medicine The establishment of a medical cyclotron facility will have the effect of - expanding the scope and capabilities of Australian nuclear medicine. Over the past decade some nuclear medicine procedures have been replaced by new technologies such as CT scanning, and some concern has been expressed regarding the future of this field. Or Potchen has pointed out that the chief attribute of nuclear medicine procedures 1s the ability to produce quantitative studies of physiological function, a capability that has not yet been achieved with other Imaging techniques (although potential exists with magnetic resonance (MRI) technology, including blood flow measurement and nuclear magnetic spectral studies focussed on limited ' regions of medical disorder. Another important attribute of nuclear medicine is measurement sensitivity. Dr Potchen believes that these attributes ensure that nuclear medicine has a unique and critical role 1n clinical practice for the foreseeable future.

2. BENEFITS TO RESEARCH AND TRAINING

I The establishment of a medical cyclotron facility would substantially expand Australian capacity to contribute to major developments in medical research, particularly to the understanding of the most prevalent and most important conditions of age-related disorders, addiction, psychiatric disorders, malignancy and heart disease. The facility would have the capacity to contribute to understanding and eventually to management and prevention of disorders which affect a large proportion of the population. The techniques do not address only limited aspects of esoteric disease conditions and the contribution to major areas of health could therefore be substantial. This would be achieved by:

making possible an Australian contribution to PET research.

expanding significantly the potential research applications of single photon emission computed tomography (SPECT) in Australia.

promoting research on tumour detection and heart disease with labelled monoclonal antibodies.

expanding the tools available to fundamental areas of research in which Australia already has excellence. supporting areas of investigation which would become possible b« ? r - including the development of new radiopharmaceuticals for research and later clinical application, chemical engineering developments associated with radioisotope production, and radiation protection and dosimetry.

Scope and Benefits of PET Research PET has a unique capability for the imaging and quantitative study of bio-chemical and physiological processes, as a result of its sensitivity, spatial and temporal resolution, and the wide range of physiological probes available. The Committee considers that this capability, at least in the short term, will make its greatest contribution in the area of research on natural function and on disease processes. As a result of the new knowledge gained through such research within Australia and overse'as, clinical management will be influenced and it may be possible to devise better treatments or even to introduce methods of prevention of many common debilitating disorders

PET research overseas is throwing new light on a wide range of disease conditions as well as normal physiology. In this report it is not intended to give a detailed account of these developments. However, to give an indication of the scope of PET research, the Committee notes some of the more interesting areas below, while recognizing that there may be others equally significant.

In studies of age-related disorders (the different types of senile dementia, brain ischaemic conditions and stroke), PET research can contribute to an understanding of how these conditions develop and how they can be prevented, it can monitor progress during patient management and can allow evaluation of the effects of treatments on diseased but still viable areas of brain tissue. PET techniques can help to differentiate between conditions, allowing the assignment of the correct therapy (where it is available) and they can assist in the development of rehabilitative strategies. For example PET studies have shown that restoration of blood circulation to the affected brain tissue after a stroke must be achieved within 24 hours if the tissue is to be salvaged. intimately, PET-based research on these disorders may contribute to reducing their high cost, by allowing for earlier discharge from hospital, defining more effective rehabilitation strategies and providing for more useful function in society following acute management of the disease. 10 Impact of PET research 1s not merely 1n Imaging or locating a lesion • • r- fbut 1n quantifying regional biochemistry and normal or disordered physiology. ^^ t % **For Instance, PET 1s showing "particular promise 1n detecting epHeptogenlc r*foci 1n partial epilepsy. Potential clinical applications for epilepsy and 'stroke are considered further 1n Section 3.

PET research 1s contributing to an understanding rf the physiological basis of psychiatric disorders, and ^n neuroreceptor studies, is being used to study the mechanisms and the effectiveness of pharmacological treatments for these disorders. Opiate receptor studies will probably be significant in * developing treatment for narcotic addiction, and i-n understanding the mechanism of addiction. From these studies could flow the knowledge that would allow preventative measures to be Introduced which may ameliorate the exceedingly costly social support systems which need to be provided today.

While most PET studies to date have been of the brain, other parts of the body are being studied. For example, PET has Important research applications in the use of 18 F-FDG and 11 C-palmitate in studies of myocardial metabolism. 0-oxygen for oxygen metabolism in any organ of the body, 0-water for blood flow, F and C labelled FOG for regional glucose ^ T metabolism and ' C methionine for studies of regional protein synthesis.

SPECT Research Like PET, SPECT 1s a technique for imaging physiological processes. It lacks the accurate quantitation and sensitivity of PET but is a lower cost technique relying on the more readily available single photon-emitting radioisotopes. Currently 14 Australian institutions are using SPECT equipment and more are planning to acquire the technology.

SPECT can be used for quantitative studies of regional cerebral blood flow, otherwise possible only with PET and perhaps with HRI. Amphetamine derivatives labelled with iodine-123 are currently considered to be the most satisfactory tracers for these studies and the availability of these derivatives in Australia would substantially expand both the clinical and research applications of SPECT. Iodine-123 and other cyclotron isotopes, particularly indium-Ill and thallium-201 are likely to be applied in a wide range of other SPECT studies Including Investigations using labelled monoclonal antibodies. The clinical applications of SPECT are considered 1n Section 3. 11 ^Labelling of Monoclonal Antibodies - .-.<-, Research on the use of labelled monoclonal antibodies for the detection __and localization of tumours and metastatlc lesions 1s giving promising results. Both 1od1ne-l23 and Indium-Ill are used 1n this area, although owing to the poorer stability of the 1od1ne-!23 label, 1nd1um-lll (which 1s currently available through Import) appears to be more suitable.

Labelled antibodies specific for CEA, alpha fetoprotein, HCG, ferritin, malignant melanoma, etc. are being studied. The tumour specificity should enable determination of the local invasion of the tumour and differentiation of tumour from -surrounding inflammation. It is expected that the tumour uptake can be used in determining the required amount of labelling with radioactivity or anti-tumour drugs needed for therapy of the tumour.

Receptor-Specific Imaging Tracers — I Use of SPECT with receptor specific Imaging tracers labelled with single 123 77 photon emitters is an important research area. For example, I and Br "^belled estrogens are undergoing clinical trials for use in testing the estrogen dependency of both primary and metastatic breast cancer. Other promising research areas are in the use of iodinated fatty acids for fatty acid metabolism, iodobenzylguanldine for neuronal uptake and storage, iodocholesterol for lipoprotein receptors, bromoperidol for neuroleptic receptors, and 3-quinuclidinyl 4-iodobenz1late for muscarinlc cholinergic receptors.

Fundamental Research Over the years Australia has established a position of eminence in several areas of fundamental research related to medicine, particularly immunology, neurology and fundamental biochemistry. However, the absence of a cyclotron facility in this country means that there is a gap in the tracers and techniques available to researchers in these areas. Consequently there is a danger that Australian work in these areas could fall behind the world effort and lose relevance. On the other hand, the establishment of a medical cyclotron facility would help to ensure that Australian research remains 1n the forefront of progress 1n these areas.

Training In addition to expanding research opportunities, the establishment of a medical cyclotron facility would expand the training opportunities for nuclear medicine physicians and otter medical researchers. 12 ln an advancing field there 1s no clear line between research and retraining« , and the research opportunities described above will for most "VKscientist $ s Involved be confined to a particular portion of their working life and thus represent training for a future (professional) application. Thus senior medical researchers will trom time to time supervise graduate students 1n their research, and tnese students will apply the skills acquired during research 1n chosen fields.

There 1s no academic department of Nuclear Medicine 1n Australia but high quality Nuclear Medicine services exist 1n most capitals (not Darwin) and 1n some major centres. Active clinical research takes place in many Nuclear Medicine departments but there is little fundamental research. The training scheme for Nuclear Medicine requires initial specialisation within the Royal Australasian College of Physicians with periods of 1-3 years accepted 1n purely research posts for the purpose of admission to Fellowship of the College.

The availability of a medical cyclotron 1n Australia would encourage trainees to spend this period of training in this scientifically productive area.

A national course in Radionuclides in Medicine is currently provided at the Australian School of Nuclear Technology at Lucas Heights. This course is not able at present to cover positron or cyclotron applications but would be able to do so if this technology were available in Australia.

Nuclear Medicine technology courses are run 1n colleges of advanced education'and institutes of technology in Victoria, South Australia and New South Wales. While the course content would need to be expanded 1t is unlikely that technologists 1n training would attend a cyclotron. However, trained technologists would be required for PET operation.

Research and Training Benefits - Summary The availability of a medium energy cyclotron, a state of the art PET machine and other necessary accessories plus staff to operate these would provide a facility with which to perform valuable research 1n many areas of 13 /I ^medicine and to make available a local centre for training purposes. In /considering a cost-benefit study of this facility, the Committee was aware of ^thV ~e" long time scale which would have to be Included If the benefits to patient > /-v "* . care were to be predicted on the basis of research investigations which are possible at present and the knowledge still to be gained from those. The impact of the research both in Australia or overseas in the longer term will lead to the development of better methods of patient care and a better quality of life for those afflicted with disease, because the research will expand the knowledge base on which advances in medicine ultimately deptnd. It will also allow preventative measures to be defined. These considerations mean that a cost benefit study of the facility would be very difficult if not impossible. Suffice to say important research could be performed and a number of people have expressed the opinion that, given the wealth and resources of this country, Australia has a duty to make a contribution to the world's storehouse of knowledge in this area. The Committee agrees with this approach and is of the opinion ^hat the benefit to be obtained from being able to use such a facility for research and training would offset any shortfall which may occur as a result of the use of a cyclotron for producing radiopharmaceuticals for routine diagnostic or therapeutic use.

3. BENEFITS TO PATIENT CARE

The establishment of a medical cyclotron facility in Australia would result in short term benefits from: the .improved availability of currently imported radioisotopes; availability of iodine-123; availability of krypton-Sim. Unfortunately the Committee has not found it possible to quantify these benefits. In the longer term there would be probable benefits from the clinical application of PET although these cannot be quantified. There might also be benefits from the clinical application of cyclotron radioisotope techniques currently still in the research phase, or yet to be developed. Such research and such developments will be much less likely if a cyclotron is unavailable in Australia.

Improved Availability of Currently Imported Radioisotopes In 1984 the numbers of patient studies performed with imported cyclotron produced radiosotopes in Australia were as follows: thallium-201 : 4240 galHum-67 : 4370 indium-Ill : 140 j?CL In the case of thallium-201, 95°/0 was used 1n myocardial perfuslon ^studies, which allow the non-Invasive detection of coronary artery disease ^through Identifying defects 1n the perfuslon of blood through the myocardium. fThalHum-201 studies complement other tests for coronary artery disease, 'Including physiological tests and technet1um-99m studies, and may be used to Identify negative cases where invasive coronary anglography would be unnecessary.

Gallium-67 is used principally for the detection and localization of hidden infection but also has a role in the delineation of tumours. Indium-Ill is used in studies of cerebrospinal fluid dynamics as well as in research. In future the labelling of blood platelets and monoclonal antibodies with indium-Ill can be expected to have clinical applications.

Thus these isotopes currently have a useful role in the management of 8750 patients annually, and the number is expected to increase. It is in the interests of patient care to ensure that supplies of the isotopes are reliable and adequate. However, nuclear medicine practitioners have emphasized to the Committee and its consultants that there are in fact frequent unscheduled delays in supply, which can disrupt patient scheduling and may result in extra days in hospital and avoidable extra costs. These are caused, for example by strikes or loss of shipments in transit. In addition, there are limitations on the availability of these isotopes (for example, they may be available only on one day in a week and patient waiting times may be as long as six weeks), and the period between ordering and delivery can be long. If these radiolsotopes were produced within Australia, they could be supplied more quickly, more frequently, and with less risk of unscheduled delays. While the risk of delays would not be entirely eliminated, a local supplier would be able to respond to problems more quickly. '

Although it has not proved possible to arrive at a quantitative estimate of the delays and interruptions to patient care occurring under the present system, the Committee considers that supplies of these isotopes would clearly be improved by local production, with resulting benefits for patient management. -"f-Rpnefits of Iodine-123 v/^r—' {§&* Iodine-123 is an important clinical radioisotope which Is currently not [^Imported because of its short half-life. For optimum usefulness it needs to , be in a high-purity form which until recently could only be prepared at a 70 * HeV cyclotron. However, a process for the production of high purity iodine-123 at a 40 HeV cyclotron has been developed in Canada and could be applied in Australia.

The Committee has identified three major potential clinical applications of high-purity iodine-123 in Australia:

SPECT brain studies using amines labelled with iodine-123; thyroid imaging and uptake studies; renal studies.

Brain Studies SPECT using certain amine derivatives labelled with iodine-123 currently appears to be the most satisfactory technique, after PET, for the measurement of cerebral blood flow and receptor binding. The technique is still regarded as investigational by the U.S. Food and Drug Administration (F.D.A.) which has not yet approved the iodine-123 labelled amine derivatives for clinical use. However, it is expected to have major clinical applications in the diagnosis, determination of prognosis and management of stroke and other cerebral ischaemic conditions. For example it could be used to determine whether brain tissue affected by a stroke could be saved by surgical or pharmacological intervention. For a range of conditions, the SPECT tecnnique would provide a means for the widespread clinical application of PET findings.

Ian Turner and Partners, following discussions with nuclear medicine physicians have estimated that if the technique had been available in Australia in 1984, it would have been applied to 7280 patients. As the number of institutions with SPECT equipment increase, the number of patients examined by this technique would be expected to increase, possibly to over 11,000 in 1989. The Committee has been unable to determine the proportion of patients whose management would be changed as a result of applying this technique.

Considerable research effort is being expended in the development of Tc labelled materials which can be used for these same conditions. If 123 this is successful then the demand for I amine derivatives is likely to be reduced considerably. 16 rhyrold Studies - Thyroid Imaging and quantitative uptake studies with radlortucUde tracers " i'ar'e of major Importance 1n the diagnosis of thyroid disorders. Ideally, Iodine radlolsotopes would be used, but the most readily available, 1od1ne-l3l, has the disadvantages that 1t delivers a high radiation dose to the thyroid and is poorly detected by gamma cameras. Iodine-123 is tha optimal isotope for thyroid studies, with a low radiation dose and emissions suitable for detection by gamma cameras. In Its absence, technet1um-99m is usually used. In 1984 a total of 14140 thyroid studies were undertaken in Australia. Of these 12420 were undertaken with technet1um-99m and 1070 with iodine-131. Iodine-131 would not be replaced for 650 thyroid metastatic surveys.

While technetium-99m delivers the lowest radiation dose of all the radioisotopes suitable for thyroid studies, it has the disadvantage that 1t 1s sometimes inaccurate for the diagnosis of thyroid cancer and in these cases a second scan needs to be performed with iodine-131. In addition high background activity results in poorer final images. The use of iodine-123 would result in the elimination of the need for second scans, and in more satisfactory imaging quality. However, it has the disadvantages of higher cost and greater inconvenience to the patient (iodine-123 needs to be injected from 2 to 24 hours before imaging whereas for technetium-99m the time between injection and scanning is only 20 minutes). In the light of the disadvantages

there may not be 100°/0replacement of technetium-99m by iodine-123 in thyroid studies. The Committee considers that the most likely level of

replacement would be about 70°/0but notes that there is no uniform opinion on this question.

Renal Studies Currently most nuclear medicine renal studies in Australia are performed with technetium-99m labelled DTPA or gluconate, but iodi,ie-131 hippuran is sometimes used. While these technetium-99m radiopharmaceuticals can be used to assess renal blood flow, perfuslon and lesion vascularity, they cannot provide a direct assessment of tubular function for which iodo-hippuran derivatives are needed. The availability of iodine-123 would ensure that tubular function could be assessed with a much lower radiation dose than that from iodine-131. These studies could be performed more often to complement technet1um-99m studies, enhancing their diagnostic value. If a satisfactory Tc radiopharmaceutical can be developed for assessment of tubular function then it would probably be used 1n preference to the more expensive 123 agent - I hippuran. 17 1984, 8260 nuclear medicine renal studies were performed in Australia, with 1od1ne-l3l-hippuran. Ian Turner and Partners have estimated that 1f ;-123-hippuran had been available 1n 1984 it would have been used 1n 700 cases, and this number would rise with time.

Benefits of Krypton-Sim The most significant benefit of krypton-Blm is that it would enhance Australian capability in the diagnosis of pulmonary embolism, a condition which is difficult to diagnose and 1s a major cause of hospital death. At present the most reliable means of diagnosing pulmonary embolism is a technique called the V/Q scan which involves a comparison of pulmonary perfusion and ventilation scans. Krypton-Blm is the optimal radioisotope for ventilation scans, which also have a role in the diagnosis of other conditions.

In the absence of krypton-Blm, xenon-133 or a technetium-99m aerosol is used for lung ventilation studies in Australia. In 1984, 7350 lung ventilation studies were carried out with perfusion studies for the detection of pulmonary embolism in Australia, with 1460 ventilation studies being

performed for other purposes. About 40°/0of lung ventilation studies were performed with technet1um-99m aerosols, the remainder with xenon-133.

In comparison with xenon-133, krypton-Blm gives much improved image quality. Perhaps its most important advantage is that when it is inhaled the patient need 'only breathe normally whereas with xenon-133 the patient must hold his breath and the procedure may need to be repeated several times. This can be difficult with ill patients and is impossible with infants. Moreover, owing to its extremely short half-life (13 seconds) krypton-Blm does not present any disposal problems, while special arrangements must be made for the disposal of xenon-133 (half-life 5 days) to ensure that occupational exposure of operators is kept low. Technetium-99m aerosols also present breathing and disposal problems, and in addition are currently believed to be considerably less accurate than the true gases.

Nuclear medicine practitioners consulted by Ian Turner and Partners were unanimous 1n their view that if krypton-Sim were available, it would totally replace technetium-99m aerosols and xenon-133 for lung ventilation studies. The Committee considers however that practical supply problems will result in a somewhat lower replacement level. 18 $The availability of krypton-Sim, and the greater ease with which it can be ^used,' is likely to lead to an increase in lung ventilation studies, resulting prom an increased use of V/Q scans and from extension of lung ventilation ^studies to new patient groups, such as patients with bronchiectasis and cystic c?fibrosis, for whom the radioisotopes currently in use are unsuitable. t *• - CVinical Applications of PET Owing to its high cost and the complex multidisciplinary support services required for its operation, PET is seen primarily as a research tool suitable for installation at a few sites only, rather than a widespread clinical tool. Nevertheless certain specialised clinical applications are expected to emerge within the next five years. In particular, it can be used in the assessment of patients with refractory epilepsy for surgery. American studies have shown that when it is used in conjunction with electroencephalographic methods it allows epileptogenic foci to be localized more readily, reducing the period of time required for the assessment of patients for surgery. The Austin Hospital has estimated that there may be 20,000 refractory epilepsy sufferers in Australia, of whom 3000 may be suitable for surgery. At the Austin Hospital National Referral Centre for Epilepsy, 56 patients were assessed for surgery in 1983.

The Austin Hospital has also pointed out the potential clinical application of PET in the assessment of stroke victims to determine the extent of tissue damage and prognosis. While both CT scanning and angiography can also be used in stroke diagnosis, PET has the advantages that it allows tissue damage to be detected much earlier, and unlike the other modalities, it provides information on tissue viability. It can be used in the assessment of patients for medical therapy to improve blood flow to the affected tissue, and for extracranial arterial bypass surgery. (The benefits of these therapeutic techniques are, however, still being evaluated).

The Austin Hospital has suggested that 900 studies a year would be performed on a PET machine, of which 100 would be routine assessments of epileptic patients, 300 routine stroke assessments, and the remainder non-routine studies. -*'~~ The Committee recognizes the potential clinical applications of PET and pts that it could play a useful role 1n patient management. However, the § ^ TnuuAer of patients which can be assessed on one machine is very small compared &S$i&*fctoJ*the^.tota" " l number 1n Australia' . The Committee considers that from a "national point of view, the most cost effective way of using a first Australian machine would be in research, which might for example lead to clinical applications which could be distributed to a larger number of patients by means of lower cost SPECT techniaues. A PET 'camera' at lower cost can be used at a site remote from a cyclotron, if it can be supplied with fluorine-18 labelled materials for positron studies.

4. COSTS ASSOCIATED WITH A MEDICAL CYCLOTRON FACILITY

In assessing the costs to the Commonwealth of a medical cyclotron facility the Committee considered the following:

capital cost of establishing the facility

annual operating costs

revenue from the sale of cyclotron produced radioisotopes

costs and savings to the health care system resulting from a cyclotron facility

costs of continuing without a cyclotron facility i It should be noted that for the organization operating a medical cyclotron facility, revenue from the sale of radioisotopes would represent income offsetting costs. However, this income is an artificial concept. Apart from export revenue, it would be derived from the Australian health care system and ultimately from the Commonwealth Government. Thus it would not represent savings for the Commonwealth as a whole. (Further details are given on page 22). 20

and Operating Costs

j|r3 The capital costs of a medical cyclotron facility include the costs of a cyclotron and associated radipisotope processing equipment, any secondary ^processing facilities required, PET equipment (if PET is incorporated in the facility), the building, installation of services, and product licensing. Annual operating costs Include salaries of professional, technical and administrative staff, power costs, maintenance, and the cost of targets for radioisotope production and other product-related consumables.

Table I gives the capital and annual operating costs for the different types of facility considered by the Committee. It is, based on estimates by Ian Turner and Partners.

Tables II and III give details of the estimated capital and operating costs for the option favoured by the Committee, the combined radioisotope production/PET facility. Estimated capital COSTS for this option are $11.04 million and operating costs $2.53 million a year.

Markets and Revenue for Cvclotron-Produced Radioisotopes , At the request of the Committee, Ian Turner and Partners attempted to quantify both the domestic and export markets which would exist for the major medically useful cyclotron radioisotopes, thalliu'n-201 , gallium-67, indium-m, iodine-123 and krypton-Blm, if they were produced at an Australian cyclotron facility. The domestic market for each radioisotope was estimated on the basis 'of extensive consultations with Nuclear Medicine Departments and in the case of the currently imported isotopes, on data collected by the Australian Radiation Laboratory. In projecting markets and revenue the consultants estimated a range from minimum to maximum, with a "most likely" figure in each case. For simplicity this report presents "most likely" estimates only, but it must be pointed out that there is a considerable degree of uncertainty in these figures, which are intended to be indicative rather than firm estimates.

A possible export market was considered to exist in the South-East Asian and Pacific regions altho ?h strong competition from other suppliers would certainly be encountered. However, in the time available it proved impossible to obtain quantitative data on the market size in the countries of these regions other than New Zealand.

In considering the domestic market for thallium-201, gallium-67, and Indium-Ill, account was taken of competition with imported products. An entirely new radioisotope production facility would have particular difficulty 21 ',

41n'.establ1sh1ng a market, at least 1n the short term, whereas the AAEC, which ^already has a place 1n the market for these radloisotopes as an Importing (agentr' , would have less difficulty• . fV,-. The consultants estimated the markets and resulting revenues which would have applied 1f a medical cyclotron had been fully operational 1n 1984, as well as projected markets and revenues for 1989. The results are summarized in Table IV. They suggest that revenue to a fully operational facility would be likely to be 1n the region of $2.5H a year.

* Approximate contributions from each Isotope ars:

I thallium-201 $0.07 - 0.15 m

gallium-67 $0.06 - 0.12 m

indium-Ill $0.01 - 0.07 m

1odine-l23 $2.00 m

krypton-Sim $0.20 - 0.26 m

The bulk of the Income would derive from sales of 1od1ne-l23, in 123 particular as I labelled amphetamines for SPECT brain studies which alone would contribute an estimated $1.7 m a year to the total income. This estimate is made on the assumption that there is no satisfactory alternative ic labelled radiopharmaceutical available for SPECT brain studies. The large contribution arises from the estimated large number of studies, the high dose per study, and the high price assigned to iodlne-123. The estimated revenue for a cyclotron facility is therefore strongly dependent on a high degree of acceptance of iodine-123 SPECT technique by the nuclear medicine practitioners which could easily prove to be grossly over-estimated. Details ^of study numbers and revenue from sales of iodine-123 in each study area are given in Table V. Appendix 3 details the basis for revenue estimates for each Isotope.

Export Market An Australian medical cyclotron facility could export radloisotopes to New Zealand and the South-East Asian region, although there would be significant competition from Japan and the USA. It has not been possible to quantify the r , 22 *">... jmarket 1n South-East Asia but the value of the New Zealand market 1s estimated [to* be" 1n the region of $A500,000-550,000. It would be comprised principally fof^the market for 1od1ne-l23 ($A450,000-500,000), with small markets for k i- , $ » ThalHum-201, gall1um-67 and krypton-Sim. This estimate must be viewed with some caution, however, as 1t assumes a very high acceptance of 1od1ne-l23, which may not be borne out 1r. practice.

Economic Appraisal - Net Present Values To make an economic appraisal of options for medical cyclotron facilities, Ian Turner and Partners determined the "net present value" of each option. This Involved determining the present ^alue of all costs and revenues, ^ discounted at the cost of capital, over a 12 year period (the economic lifetime of a cyclotron). Revenues were subtracted from costs to give the net present value, with minimum, maximum and most likely values being estimated. The results are summarised in Table VI. All "most likely" values were negative, .indicating that for all options returns are unlikely to cover costs. For options including PET, the results were affected substantially by the income attributed to PET. It is unlikely however that any Income would be derived from PET, at least in the short term. The analysis does not Include export markets.

Costs to the Health Care System The availability of locally produced cyclotron radlolsotopes will result in additional costs to the health care system, arising from:

the substitution of cyclotron isotopes for less satisfactory reactor i Isotopes in existing tests - the additional cost would approximately consist of the difference 1n prices between the isotopes;

the Introduction of new tests using cyclotron isotopes - the additional costs would approximately consist of the cost of the Isotopes plus the fees for performing the .tests.

These costs would be met either from hospital budgets provided by State Governments and ultimately by the Commonwealth, or from Medicare. Thus all costs would ultimately be a charge to the Commonwealth Government. Costs arising from the prices paid for the isotopes themselves would 1n represent a transfer from one Commonwealth body to another, and would not a real cost for the Commonwealth as a whole. However, the additional 'services and any procedures resulting from them would represent a real additional cost to the Commonwealth.

If the estimates given nn p. 14 of the level of usage of iodine-123 SPECT brain studies are correct, these studies would make the largest single contribution to the additional costs to health care. They would all fall into the category of new tests, rather than substitutions for existing studies. On the basis of the study numbers given in Table V, the isotope cost and dosage given in Appendix 3, and the assumption that the cost of performing each study would be $150, they would have added a total of $2.84 million to the cost of health care in 1984, including $1.75 million for the cost of the isotope and $1.09 million for the cost of the service. In 1989 the total cost would be $3.42 million.

The additional cost of using iodine-123 in thyroid studies would be the difference between its cost and the cost of the isotopes substituted (technetium-99m or iodine-131), estimated at $137,000 in 1984. It is not anticipated that there would be any costs arising from additional tests. The use of iodine-123 in renal studies would involve some additional tests as well as isotope substitution, with costs estimated at $122,000 in 1984. The availability of krypton-Sim for lung studies may also result in the performance of additional tests as well as the cost of isotope substitution. The estimated additional cost in 1984 would have been $251,000. As gallium-67, thallium-201, and indium-Ill would be substituting for imported products, it is not anticipated that their local production would add to the cost of health care, provided their prices are similar to those of the imported products.

The additional costs to health care resulting from the local production of iodine-123 and krypton-Sim are summarized in Table VII.

The introduction of PET would lead to additional costs to health care if it is applied clinically. At least in the short term, however, it would be expected to remain a cost to research.

Additional costs to medical research, other than capital and operating costs of a ryciotron/PET facility, may ari:s in the area of PET and other areas involving cyclotron radioisotopes. Alternatively research grants in these areas may replace grants in others. pavings for the Health Care System itf -'These additional costs may be offset by savings for health care, arising from:

. t. -;reduced hospital stays resulting from more timely performance of tests and more accurate diagnosis

enhanced capacity to select appropriate treatment, for example, for reversible stroke

In some cases the enhanced diagnostic capacity may contribute to the rehabilitation of patients who would otherwise be permanently disabled, at substantial cost to health care. It was not possible to quantify the cost savings which could be directly attributed to the availability of cyclotron radlolsotopes.

Costs of Continuing without a Cyclotron The Committee has found that there would be costs associated with remaining without a cyclotron, although again these are difficult to quantify. The Committee has identified the following:

loss of foreign exchange associated with Importing radioisotopes; loss of Australian trained experts overseas who might have remained 1n Australia if cyclotron Isotopes and PET were available the cost of not being able to apply 1n Australia overseas training in the use of cyclotron isotopes or PET acquired by nuc.lear medicine practitioners or medical researchers; the sub-optimum utilization of existing SPECT equipment.

Dr Potchen has estimated that approximately 5 of the 10 medical investigators permanently "exported" overseas each year may have remained in Australia if a cyclotron/PET facility had been established. The total cost of training 5 medical investigators may be in the region of $1.7 million.

About 10°/0 of nuclear medicine practitioners go overseas each year for additional training, at substantial cost to their employing Institutions. Host return, but a significant number have acquired experience in the use of cyclotron radioisotopes which they are subsequently not able to apply 1n Australia. 25

TABLE 1: CAPITAL AND OPERATING COSTS OF HED7CAL CYCLOTRON FACILITIES

Option Capital Cost Annual Operating Cost (excluding capital charges and depredation) $A million $A million 40 HeV cyclotron facility for radiolsotope production only 8.077 1.589 40 HeV cyclotron facility for radioisotope production and PET 11.038 2.531 16 HeV cyclotron facility fo- PET only 5.553 1.030 Separate facilities for radioisotope production and PET 13.630 2.619

Notes: Full details of estimates are given in the report to the Committee by Ian Turner and Partners. Estimates are in 1985 dollars and are based on exchange rates at 1 Harch 1985. In estimating capital costs it was assumed that some radiopharmaceutical processing facilities were already available. The cost of raw materials and other consumables will depend on the level of radioisotope production. The costs for this item were estimated on the basis of Ian Turner and Partners' estimates of "most likely" sales of radioisotopss 1n 1989. Salary, power costs and maintenance will vary with the number of shifts worked per day. The above estimates were based on the following assumptions: » . a cyclotron for radioisotope production only would operate on 2 shifts a day . a facility combining radioisotope production and PET would operate on 3 shifts a day (2 for isotope production and 1 for PET) a PET facility would operate on 1 shift a day 26

TABLE II. DETAILS OF CAPITAL COSTS FOR A COMBINED RADIOISOTQPE PRODUCTION/PET FACILITY

Equipment and Related Costs $A million Cyclotron - basic unit, accessories/1) freight, Insurance, installation 3.559 Cyclotron systems development 0.350 Factory supplied staff training 0.050 Hot cells 0.600 PET - camera, installation and commissioning 2.245 Contingency 0.340

SUB TOTAL 7.144

Building and Services

Building 1.643

Building services^) 0.585

Design costs 0.320

Contingency 0.246

SUB TOTAL 2.794

Additional facilities for secondary radlopharmaceutical processing 0.500 Product licensing 0.600

TOTAL 11.038

Notes; (1) Accessories include beam line transport system, chemical processing system, multi target support, cooling water system. (2) Building services include water cooling system, air conditioning, electrical services, compressed air and gas services, waste disposal, and holding tank. 27

TABLE III: DETAILS OF ANNUAL OPERATING COSTS FOR A COMBINED RADIOISOTOPE PRODUCTION/PET FACILITY

« Staffing CostsO) *A million Salaries^2) 0.880 Salary overheads 0.176 Contingency 0.106 SUB TOTAL 1TT62 Power costs 0.190 Maintenance Building 0.022 Building services 0.041 Cyclotron equipment 0.370 PET equipment 0.189 I SUB TOTAL 07622 Raw Materials and Consumables Commercial radioisotope production^3) 0.417 PET 0.140 SUB TOTAL OsT

TOTAL 2.531 Notes: (1) Staffing requirements are estimated on the basis of 2 shifts a day for radioisotope production and 1 shift a day for PET. (2) The total number of staff required is estimated by Jan Turner and Partners at 39, comprising: . 7 administrative staff (including a clinical director and an operations director) . 7 scientific professionals . 12,engineers and maintenance staff . 8 technicians . 5 medical staff (including a staff specialist and a registrar) (3) The cost of raw materials and consumables for commercial radioisotope production is estimated on the basis of 20°/o of sales up to $1 million, and 15°/° of sales over $1 million. 28

TABLE IV: ESTIMATED "HOST LIKELY" MARKETS AND REVENUES FOR CYCLOTRON RADIOISOTOPES PRODUCED IN AUSTRALIA

Radloisotope Numbers of Studies Revenue (W • 1984 1989 1984 1989 (notional) (notional)

Thallium-201 4240 5290 146300 71400 Gallium-67 4370 6000 121000 55600 Indium-Ill , 156 706 11300 73900 Iodine-123 18120 25540 1,990,400 2,039,500 Krypton-Sim 8736 11232 256600 206400

TOTALS 35622 48768 2,526,600 2,446,800

Notes: Estimates are in 1985 dollars (exchange rate at 1 March 1985). Revenues for 1989 are given in present values and have been calculated using a 10% discount factor. , 1984 figures are estimates of the markets and revenues which would have been likely for a notional cyclotron radioisotope production facility if it had been fully operational in 1984.

TABLE V: ESTIMATED "HOST LIKELY" STUDY NUMBERS AND REVENUES FOR IODINE-123 IN DIFFERENT APPLICATIONS

Application Number of Studies Revenue, }A 1984 1989 1984 1989 - (notional) . (notional)

Brain Studies 7280 11440 1,744,000 1,710,000 Renal Studies 700 870 85,000 65,000 Thyroid Studies 10140 12680 162,400 127,000 Cancer Diagnosis (MCA Labelling) 550 137,500

TOTALS 18120 25540 1,990,400 2,039,500 29

TABLE VI: NET PRESENT VALUE OF OPTIONS FOR MEDICAL CYCLOTRON FACILITIES

Option Net Present Value ($A million) Minimum Maximum Most Likely no cyclotron -,8.3 - 7.5 - 7.9 40 HeV cyclotron-radioisotope production only - 7.5 + 4.0 - 3.7

40 MeV cyclotron-radiolsotope production •*• PET - assume no Income from PET - 17.0 - 5.5 - 13.2 - assume Income of $1.8M p.a. from PET - 4.7M + 6.8 - 0.9 16 HeV cyclotron-PET only - assume no income from PET - 12.5 - assume income of S1.8M p.a. from PET - 0.2 Separate facilities 40 MeV cyclotron-radi oi sotope producti on, 16 MeV cyclotron for PET - assume no income from PET - 20.0 - 8.5 - 16.2 - assume income of $1,8M p.a. from PET - 7.7 + 3.8 - 3.9 30

TABLE VII: ADDITIONAL COSTS TO HEALTH CARE

Application Costs, $A

1984 (notional) 1989

* Isotopes Services Total Isotopes Services Total

Iodine-123 - Brain 1,747,200 1,092,000 2,839,200 1,710,000 1,710,000 3,420,000 - Renal 80,000 42,000 122,000 61,000 59,000 120,000 - Thyroid 137,000 - 137,000 101,000 - 101,000 Krypton-Sim 132,000 119,000 251,000 34,000 153,000 187,000

TOTALS 2,096,200 1,253,000 3,225,900 1,906,000 l',922,000 3,828,000

Notes: The following fees per study were assumed:- Iodine-123 brain study : $150 Iodine-123 renal study : $100 Krypton-Sim lung ventilation study : $85 Following costs per study were used for substituted isotopes:- Iodine-131 (renal) : $14.05 Technetium-99m (thyroid) : $ 2.25 Iodine-131 (thyroid) : $ 4.50 Xenon-133 (lung) : $20.40 Technetium-99m (lung, aerosol) : $ 7.50 31

5. SITING AND MANAGEMENT

The foregoing discussion has Indicated that the proposed cyclotron facility is intended to fulfil the dual functions of

a resource to support medical research, by providing tools such as short lived positron emitting isotopes and PET not otherwise accessible to front line researchers in Australia t a resource for the routine production of short-lived isotopes for diagnostic use throughout Australia

It is desirable therefore that the cyclotron be sited at a location with ready access to a major teaching hospital or medical centre, which would be expected to provide strong academic support for its programs. However, as medical research institutions elsewhere in the country should have comfortable access, the cyclotron with its supporting laboratory and technical resources should be viewed as a national facility. The complete facility will therefore need to provide laboratory and office space for visiting researchers and access to the full range of medical facilities and specialised diagnostic services likely to be found only in a major centre. Moreover, to realise the full potential of radioisotopes with very short half-lives (minutes to several hours) there will need to be appropriate technical resources (hot cells) and staff capable of using fast processing techniques with suitable quality control to convert irradiated targets into radiopharmaceuticals suitable for administration to patients. I For the second function - the routine production and distribution on a reliable basis of cyclotron based radiopharmaceuticals for diagnostic use - the half-lives are somewhat longer and off site processing can be contemplated provided that it is not too distant from the cyclotron. The processing and distribution of such radioisotopes requires considerable expertise in production, programming and the safe manipulation and transport of high levels of radioactivity.

There are some commercial firms in Australia with wide experience 1n 1 distributing isotopes, which have been prepared by their overseas principals, —II u but none of these have direct experience 1n their preparation. 32

The Australian Atomic Energy Commission (AAEC) has been preparing and selling a range of reactor produced Isotopes for about twenty f}ve years and 1s therefore well positioned to .expand Into the area of cyclotron produced Isotopes. Consequently the Committee felt that there was good justification to recommend that the AAEC should be responsible for the processing and distribution of cyclotron produced radiopharmaceuticals. The Committee believes that the proposal presented by the AAEC at the Workshop, Canberra, December 1984 for a national medical cyclotron facility sited at Royal Prince Alfred Hospital, Camperdown, NSW, is realistic. This site co^d satisfy the requirements of a national facility outlined above, and is close enough to allow irradiated targets to be transported to the AAEC where they could be processed with existing hot cells and other resources currently used for reactor produced rad^oisotopes.

The creation of a national facility, embracing a broad range of research Interests and with some additional Isotope production responsibilities creates a set of conditions requiring sensitive and skilful management. Since in general only one radioisotope can be prepared at a time and replacement of targets, Ion source filaments, etc., is time consuming, the number of research studies (which will frequently Involve patients) carried out in a normal day will be limited. Irradiation times of several hours are generally required for the longer half-life isotopes and these may be best performed out of normal hours. As demand grows it is likely that twenty four hour operation will be required. In any case the distribution timetables for commercial isotopes will require that in the main they be produced outside of normal hours. The Board of Management (see below) will therefore have to provide clear guidelines and policy directives to ensure that the facility is exploited to maximum advantage. For out of hours operation, during which isotopes will be produced mainly for commercial purposes, the details of machine use will be partly shaped by the needs of the market.

The availability of cyclotron produced isotopes will strengthen and widen the multidlsciplinary interests of nuclear medicine. Such isotopes can lead to a wide range of research opportunities through additional functional tracer imaging of many areas of the body - cardiovascular, pulmonary, central nervous system, renal, gastric, bone etc. In addition they can be used 1n tumour studies, studies of glucose metabolism, response of tumours to therapy, stroke staging, evaluations of epilepsy etc. It 1s clear that there is potential for a wide variety of requests to exploit a cyclotron/PET facility and that 33 problems could arise 1n the management of the facility due to the conflicts of interest between production and research activities. For this reason, it is suggested that control of the facility be firmly vested in a Board of Management, with a wide ranging membership which includes the Resources and Energy and Health portfolios, hospital and appropriate professional bodies.

The Board of Management will need to meet frequently to guide those responsible for the day-to-day running of the facility (the manager and staff), and to ensure that the relative priorities of research and diagnostic demands are clearly and sensibly resolved.

There is a further issue, which lies at the fringe of the Committee's terms of reference, but which nevertheless requires comment. The introduction of a substantial resource of this nature, with significant potential impact on medical research 1n Australia carries implications for research funding which have not been directly addressed. At the present time there is only limited research being carried out in Australia in nuclear medicine and related fields. It has been argued that this 1s in part due to the lack of appropriate resources, which the present proposal seeks to redress, and that as cyclotron produced isotopes became available researchers in many fields will take advantage of them. Such an outcome, which is part of the purpose of having a medical cyclotron in Australia, carries further research funding implications. The Committee feels the need to draw attention to the fact that any such funding will need to be assessed in the normal way, in competition with research proposals from other fields of medical research, and through procedures which are under the control of the National Health and Medical Research Council. Indeed, in the final analysis, the commitment of resources of this magnitude requires that the concept be assessed 1n competition with proposals from other fields of medical research, which may be seeking similar resources. 34

6. CONCLUSIONS AND RECOMMENDATIONS

After reviewing the information made available to 1t by the consultants, the Cyclotron Workshop and from Us own enquiries, the Committee came to the general conclusion that the case for a medical cyclotron rests on Its potential Impact on research and training 1n nuclear medicine and other medical disciplines, rather thaji. the routine provision of short lived Isotopes. While a cyclotron would provide benefits in routine patient management, no compelling case was presented to support a cyclotron from this perspective alone. Rather, the view was expressed that there were areas of medical research in which Australia currently holds an eminent position and this would be enhanced if short-lived cyclotron based isotopes were to become available. Conversely the same position might be imperilled in the future if they were not. It was assumed that there would be at least one location, close to the cyclotron itself, with high quality PET equipment, together with the usual repertoire of diagnostic services found in a major medical centre.

Thus the Committee recommends -

The establishment of a national medical cyclotron to provide a supply of short-lived radioisotopes for research in relevant fields of medicine, and for diagnostic use in nuclear medicine.

•+ An Australian cyclotron would provide benefits in routine patient * i » management by making available for diagnostic use short-lived isotopes not presently available, or only available as imports with some supply problems. Methods of management devised as a result of studies using short-lived isotopes might also be used to the benefit , of other patients who may not need the same investigations.

The Committee accepted the view that advantage should be tajcen of the Australian Atomic Energy Commission's experience in the processing and distribution of reactor-produced radioisotopes, and finds merit in the joint proposal by the AAEC and Royal Prince Alfred Hospital that a cyclotron centre be established in the ground of R.P.A.H., with resources and services to support local and visiting research workers. It was further of the opinion that the availability of fluorine-18 from the cyclotron for distribution to other centres would provide satisfactorily for limited PET studies, at least for the immediate future. The Committee concludes therefore that

The Royal Prince Alfred Hospital is seen as the most appropriate teaching hospital for the cyclotron facility.

The estimated capital cost of the cyclotron facility (March 1985) is $M11.0, with annual recurring costs of approximately $M2.5. These figures include the capital and operating costs of equipment for positron emission tomography (PET), to be deployed at the cyclotron facility, using very short lived isotopes. The Committee believes that PET is likely to develop as a research and diagnostic tool of great importance in the future. It also considers that the availability of fluorine-18 from the cyclotron could provide a satisfactory basis for limited PET studies at other locations.

The Committee has^ some concerns that there is potential for conflict of purpose in a facility designed to satisfy both research and isotope production needs, and urges therefore the establishment of a strong Board of Management, to provide the manager and staff with clear guidelines governing Us use. In addition the Committee feels that it should draw attention to the fact that resources made available for research using cyclotron resources should only be provided following the normal 'peer competition'. Similarly the cyclotron itself should be subject to the same scrutiny in the competition for medical research resources. 36

Accordingly,

The cyclotron facility should be administered by a manager and staff responsible to a Board of Management drawn from the user community and other relevant Institutions. Research associated with the cyclotron should be subject to peer review and should compete for funding support 1n the normal way. .

The Committee recognises that, however sound the case, a proposal for a medical cyclotron must be, assessed 1n the context of competing requests for resources to support medical research and services.

Bibliography 1. Medical Cyclotron Facilities. A report by The National Health Technology ^dv^sory Panel. September 1984.

2. Australian Medical Cyclotron Workshop Papers, Dec. 1984.

?j. E.J. Potchen and D.A. Gift; Costs and Benefits for Australian Health Care of Cyclotron Radioisotope Production and Positron Emission Tomography. Feb. 1985.

4. Ian Turner and Partners: Financial Analysis of Options for Medical Cyclotron Facilities 1n Australia. March 1985. 37

APPENDIX 1

MEDICAL CYCLOTRON COMMITTEE

Chairman. Cr K Lokan Director Australian Radiation Laboratory

Members Representing National Health Technology Advisory Panel:

Mr P Gross Director Institute of Health Economics and Technology Assessment

Dr D M Hailey Assistant Director-General Department of Health

Representing National Health and Medical Research Council:

Professor R Porter Director John Curtin School of Medical Research Australian National University

Mr P Griffin Assistant Director-General Department of Health 38

Representing Department of Resources and Energy:

Hr J Carlson Assistant Secretary Nuclear Affairs Branch I

Representing Royal Australasian College of Physicians:

Dr F Lovegrove Sir Charles Gairdner Hospital Perth

MEDICAL CYCLOTRON COMMITTEE TERMS OF REFERENCE

The Committee should examine the need for a national medical cyclotron facility in Australia. It should assess the costs and benefits for Australian health care and other implications of options for medical cyclotron facilities which might be developed, including the AAEC/Royal Prince Alfred Hospital and Austin Hospital proposals. The assessment should include cyclotron radioisotope production, processing and distribution, and positron emission tomography. Particle beam therapy should be commented on.

During the assessment the Committee should take into consideration the relationship between a medical cyclotron facility and the Australian nuclear science and technology infrastructure.

On the basis of the assessment the Committee should make recommend^ Ions to the Commonwealth .Government on.whether establishment of appropriate medical cyclotron facilities is justified, and if so advise on the most suitable of the options considered.

During the assessment the Committee should, in particular:

Identify the benefits for patient management and outcome of cyclotron-produced radioisotopes and PET, with, if possible, some quantification. 39 assess the opportunities that cyclotron-produced radlolsotopes and PET would provide for Australian medical research and tralnlnq.

estimate the capital and operating costs of the options considered, the likely revenue from sales to the domestic and export market for cyclotron-produced radiolsotopes, and the economic Impact of previously unavailable radlolsotopes and PET on Australian health services, Including added costs and cost savings.

Identify the most cost effective options for medical cyclotron facilities and the optimal siting and management arrangements.

The assistance of consultants should be drawn on as required 1n the study. 40

APPENDIX 2

Terms of Reference of Consultants to Medical Cyclotron Committee

i ———•FINANCIA——L—^— ANALYSI——————S OF ^—^——^^OPTIONS FO—R i HEDICAL CYCLOTRON FACILITIES

TERMS OF REFERENCE

The Consultant Is to report to the Medical Cyclotron Committee on the costs of, and revenue from a range of possible cyclotron/PET facilities in Australia.

The report is to cover the following matters:

(1) estimates of the capital and operating costs of:

(a) medical cyclotron facilities for radioisotope production, processing and distribution only.

(b) medical cyclotron facilities both for radioisotope production, processing and distribution, and for PET.

(11) likely selling prices of cyclotron-produced radioisotopes and charges for PET. , (iii) the current and projected size and value of domestic and export medical and Industrial markets for radioisotopes produced at a cyclotron in Australia, taking into account competition from overseas suppliers and the existence of excess capacity overseas. (Radioisotopes of particular interest include gallium - 67, krypton - 81m, indium - 111, iodine - 123 and thallium - 201. 41

Other radloisotopes of Importance for positron emission tomography are carbon - 11, nitrogen - 13, oxygen - 15 and fluorine - 18).

The Issues canvassed should Include:

(a) the contribution of clinical diagnostic and medical research applications to the domestic medical market.

(b) the likely penetration of iodine - 123 into the technetium - 99m and iodine - 131 thyroid scan market. A comparison with overseas experience and data is to be provided.

(c) the possibility of importing high purity Iodine - 123 and the effect of this possibility on the market for locally produced iodine - 123.

(d) the likely market for iodine - 123 labelled compounds for diagnostic purposes.

(e) where the production of a radioisotope can be based on a nuclear reactor or a cyclotron, the likely extent of substitution of the reactor product by a cyclotron product.

(f) the likely market penetration of locally produced gallium - 67, indium - 111 and thallium - 201 in competition with imported products.

(iv) on the basis of the market analysis, estimate of the' revenue to a cyclotron facility from radioisotope sales. 42

COSTS AND BENEFITS FOR AUSTRALIAN HEALTH CARE OF POSITRON EMISSION TOMOGRAPHY

TERMS OF REFERENCE

The consultant is to report to the Medical Cyclotron Committee on the benefits for Australian health care of a positron emission tomography (PET) facility and costs to the health care system (other than capital and operating costs).

In particular the consultant should:

assess the current status of the use of PET overseas in the evaluation of disease conditions in terms of whether it is in the research phase or ready for routine clinical application.

assess the potential of PET in the management of disease conditions in Australia, e.g.

determine the potential contribution of PET to the evaluation of epilepsy patients for surgery, including any cost savings.

- ' assess the contribution of PET to the management of stroke patients, identifying and if possible quantifying patient benefit, and any cost savings.

comment on likely trends in the development of the technology and on future benefits that would flow from technological advances.

identify possible alternative modalities (including SPECT) and report on their costs and efficacy.

compare the advantages and disadvantages of a stand-alone PET facility with a facility associated with a cyclotron also used for commercial radioisotope production.

The Issues raised in the NHTAP Report on Medical Cyclotron Facilities should be taken Into account during the study. 43

COSTS AND BENEFITS FOR AUSTRALIAN HEALTH CARE OF CYCLOTRON RADIOISOTOPE PRODUCTION

* TERMS OF REFERENCE

The consultant 1s to report to the Medical Cyclotron Committee on the costs and benefits for the Australian health care system which would result from the production in this country of cyclotron radloisotopes for use in nuclear medicine.

The report should identify the following:

any added costs to the health care system from increased use of radioisotopes resulting from increased availability, and from the use of previously unavailable radioisotopes (Iodine - 123 and krypton - 81m).

any cost savings to health care from the local availability of previously imported radioisotopes (thallium - 201, gallium - 67 and Indium - 111).

any cost savings resulting from the replacement of other diagnostic techniques by these radioisotopes.

possible alternatives to the use of radioisotopes, their costs and efficacy.

the benefits for patient management and outcome resulting from the use of previously unavailable radloisotopes, e.g.

any extension to the diagnostic techniques available or Improvements 1n diagnostic accuracy and their effect on efficacy of treatment, mortality, morbidity, length of hospital stay;

any reduction 1n radiation hazard to patients and/or health workers and the effect of such reduction in terms of reduced incidence of radiation-induced disease conditions. 44

(Benefits should be quantified as far as possible but not necessarily expressed 1n dollar terms).

It should also Include comment on trends 1n scientific and technological developments related to the use of cyclotron-produced radlolsotopes and on future benefits that would flow from these advances.

Areas for particular attention Include the use of Iodine - 123 1n thyroid % studies and single photon emission computed tomography, and the use of krypton - 81m 1n the diagnosis of pulmonary embolism.

The issues raised in the NHTAP Report on Medical Cyclotron Facilities should be taken into account during the study. 45

APPENDIX 3

Revenue Estimates for Cyclotron Produced Isotopes.

I The following are the 'Most Likely' market revenue estimates for the five 123 most commonly used radiolsotopes. Iodine 1s the largest component and Its use 1s shown 1n greater detail.

The five radioisotopes are:

IodinT A- e123 Thalliu-ru 114 m2 Gallium IndiuT Jt m 81m Krypto„ * n

The estimates are derived from the report 'Financial Analysis of Options for Medical Cyclotron Facilities1, prepared for the Medical Cyclotron Committee by Ian Turner and Partners.

123 IODINE

1. BRAIN STUDIES 1984 1989 Number of studies 7280 11440 Average dosage per study * 3 mCi 3 mCi Market estimate in mCi 21880 34200 Price per mCi, $A 80 50 Market Revenue $A 1750400 1710000

Range of dosage 2-10 mCi

2. RENAL STUDIES Number of studies 700 870 Average dosage per study * 1.5 mCi 1.5 mCi Market estimate in mCi 1050 1300 Price per md JA 80 50 Market Revenue $A 84000 65000

Range of dosage 1.5-2.00 mCi per study. 46

THYROID STUDIES 1984 1989 Number of studies 10140 12680 Average dosage per study * 0.2 mC1 0.2 mC1 Market estimate 1n mCi 2030 2540 Price per mCi JA 80 50 Market Revenue $A 162400 127000

4. CANCERS 123 I will be substituted for Indium111 up to 50V, for certain cancer studies 1n 1989 Number of studies 500 Market estimate in mCi 2750 Price per mCi JA 50 Market Revenue JA 137500

Range of Dosage 0.1-0.5 md

SUMMARY - I Total number of studies 18120 25540 Market Estimate in mCi 24960 40790 Market Revenue $A 1996800 2039500

THALLIUM - 201 Used mainly in myocardlal studies

Number of studies 4240 5290 Average dosage per study 2 mCi 2 tnC1 Market share in mCi 4250 (1) 5290 (1) Price per mCi $A 34.50 13.50 Market Revenue $A' 146300 .71400

(1) 50°/0 of the total market estimate of 8480 and 10580 mCi, respectively. The other 50°/0 would be imported. 47

GALLIUM - 67 Used mainly in Tumour and Abscess studies

* 1984 1989 Number of studies 4370 6000 Average dosage per study 5.55 mCi 5.5 mCi Market share in mCi 16800 (2) 23170 (2) Price per mCi JA 7.20 2.40 Market Revenue $A 121000 55600

(2) 70°/0 of the total market estimate of 24000 and 33100 mCi respectively. The other 30°/0 would be imported.

INDIUM - 111 Used mainly in CSF, Cancer and Blood Studies.

Number of studies 156 706 Average dosage per study 1.5-5 mCi 1.5 mCi Market share in mCi 105 (3) 1480 (3) Price per mCi JA 107.50 (4) 49.90 (4) Market Revenue $A 11000 73990

(3) 50°/0 of the total market estimate of 210 and 2960 mCi respectively.

The other 50°/0 would be imported.

(4) Calculated average price of three Indium-Ill radiopharmaceuticals: In -111 - DTPA, In -111 - Oxine. and In -111 chloride.

KRYPTON 81m Used in lung studies

Number of studies 8736 11232 Number of studies per generator 8 8 Market estimate of generators 1092 1404 Price per generator 235 147 Market Revenue $A 256600 206400 r- t- 48

NOTES

Estimates are 1n 1985 dollars (exchange rate of 1 March 1985). « Revenues for 1989 are given 1n present values and have been calculated

using 10°/0 discount factor.

1984 figures are estimates of the markets and revenues which would have bsen likely for a notional cyclotron radlolsotope production facility 1f it had been fully operational in 1984.